Afatinib (systematic name: N-{4-(3-chloro-4-fluoro-anilino)-7-[(tetra-hydro-furan-3-yl)-oxy]quinazolin-6-yl}-4-(di-methyl-amino)-but-2-enamide), is a specific in-hibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from aceto-nitrile as a mixed water-aceto-nitrile solvent, C24H25ClFN5O3·0.25C2H3N·2H2O. It crystallizes with two independent mol-ecules (A and B) in the asymmetric unit of the chiral space group P4212, but exhibits close to perfect pseudo-inversion symmetry, emulating P4/ncc that relates the two mol-ecules to each other. Exact inversion symmetry is however broken by swapping of oxygen and CH2 moieties of the outer tetra-hydro-furanyl substituents of the two independent mol-ecules. This can, in turn, be traced back to C-H⋯N and C-H⋯O inter-actions of the aceto-nitrile solvent mol-ecules with the tetra-hydro-furan oxygen and CH2 units. In the crystal, neighboring mol-ecules are connected via N-H⋯O hydrogen bonds between the secondary amine and the amide keto O atom. Additional hydrogen bonds are formed through the water solvent mol-ecules, which are engaged in O-H⋯O and O-H⋯N hydrogen bonds connecting to the di-methyl-amino N atom, the amide keto O atom, and one of the quinazoline N atoms of a neighboring mol-ecule, leading to an intricate three-dimensional hydrogen-bonded superstructure. There are two types of channels stretching along the direction of the c axis; one along the fourfold rotational axis, occupied by aceto-nitrile solvent mol-ecules situated on that axis, and parallel channels which are not occupied by any solvent.
Keywords: ErbB tyrosine kinase inhibitor; crystal structure; hydrogen bonding; pseudo-inversion center; pseudo-symmetry.